White Matter Disorganization in Brain Correlated With Poor Reading Fluency

The inability to rapidly and smoothly process serial words has long been a bane to many students and remediation tutors. Now Harvard researchers are on the cusp of understanding how specific brain malformations may lead to poor reading fluency.

The scientists used diffusion tensor imaging, a form of MRI that captures how water diffuses around myelin sheaths, to find a correlation between disorganized white matter tracts and difficulty in reading, which they report in the Dec. 4 Neurology.

Courtesy Bernard Chang

Pattern for poor reading. MRIs of a normal brain (left) and a brain affected by periventricular nodular heterotopia (PNH) point up gray matter in the PNH brain that has failed to migrate to the outer brain during fetal development (arrows). The result is misplaced gray matter and unorganized white matter tracts. Patients with PNH have difficulty with reading fluency, which may be caused by the unorganized white matter.

The scientists studied two groups of patients who had brain disorders preventing normal reading, the first including people with dyslexia. The second group, patients with periventricular nodular heterotopia (PNH), were born with brain malformations. In the fetal life of PNH patients, specific neurons fail to migrate to the periphery of the brain and instead stay deep in the middle.

“The amazing thing about PNH is that even though patients have large nodules of misplaced gray matter, they essentially, on the surface, seem quite normal,” said Bernard Chang, an HMS assistant professor of neurology at Beth Israel Deaconess Medical Center who co-led the study with Tami Katzir, a dyslexia specialist who was at the Harvard Graduate School of Education when the research was performed. Many PNH patients have ordinary intelligence, but begin experiencing seizures during adolescence. Their characteristically placed brain nodules allow them to be easily diagnosed via MRI.

In a 2005 paper, Chang, with senior author Christopher A. Walsh, Howard Hughes investigator and the Bullard professor of neurology at BID, and colleagues, described their study of 10 PNH patients, finding that they had difficulty with the processing speed of reading.

“That made us wonder, why would misplaced gray matter like this lead to a specific problem with reading?” said Chang, “and was this in any way related to dyslexia?”

In their current study, the researchers compared reading skills in 10 patients with PNH, 10 with dyslexia, and 10 normal subjects. After a battery of reading tests and brain imaging, the scientists found that the dyslexics and the PNH patients shared a specific problem relating to both reading fluency and disorganized white matter tracts.

The more disorganized the white matter tracts, the poorer the reading fluency. Chang said that until they learned that PNH patients had problems with reading, he never thought to use the disease as a model to understand reading fluency in dyslexia.

“Because dyslexia is so common and has so many different subtypes and is so heterogeneous, it can make it hard to identify specific features that tie into specific aspects of reading,” he said.

Indeed, the reading tests showed that dyslexics had more trouble with phonological tests—breaking down words into sound segments—in addition to reading-fluency exams. When given more time, both the PNH patients and the dyslexics performed nearly as well as the normal readers.

If students with dyslexia and other reading disorders are found to have unorganized white matter tracts, then tutors might, for example, use a variety of approaches to specifically improve processing speed, said Walsh, also an HMS professor of pediatrics at Children’s Hospital Boston.

“The clinical implications of this study are that assessment and treatment of reading disabilities should include not just measures of reading accuracy but also measures of reading fluency,” said Katzir.

—Laura Geggel

Blood Stem Cells Reinforce Local Immune Defense

Scientists have generally viewed hematopoietic stem cells (HSCs) as having the singular role of remaining in the bone marrow until called upon to replenish blood and immune system cells.

But new research from the lab of HMS professor of pathology Ulrich von Andrian, published in the Nov. 30 Cell, suggests that HSCs’ biological role is far more versatile and dynamic. He and his colleagues have found that these cells can travel from the bone marrow, through the blood, to visceral organs, where they reconnoiter for pathogenic invaders. Upon encountering the enemy, they differentiate locally into whatever myeloid lineages are needed to mount a defense.

“This process changes the way we look at blood stem cells,” said von Andrian.

For almost five decades scientists have known that a fraction of HSCs sometimes migrate from the bone marrow into the bloodstream. And while scientists have observed this phenomenon, they have not known exactly why or what sort of itinerary the cells follow once in the blood.

To explore these questions, a group in von Andrian’s lab, led by postdoctoral researcher and cardiologist Steffen Massberg, extracted lymph samples from the thoracic duct of experimental mice. A major component of the lymphatic system, the duct routes excess fluids accumulating in the organs into the circulation.

After screening large samples of thoracic fluid, the researchers discovered an extremely small population of cells that, after rigorous testing, behaved identically to blood stem cells. Further tests, which involved mice genetically engineered so their blood stem cells could be detected through fluorescent microscopy, revealed that these cells were also scattered throughout visceral organs such as the liver, heart, and lung.

“Taken altogether, a picture developed suggesting that these cells migrated from the marrow and into the circulation, where they would then leak out and enter the tissue,” said Massberg. “After that, the thoracic duct would empty them back into the circulation, where they could reenter the marrow. But the question was, why? What exactly are they doing?”

The group found that the stem cells remain in the tissue for 36 hours before exiting into the thoracic duct. This suggested that the cells were conducting some kind of surveillance. To test this, Massberg and colleagues injected a bacterial endotoxin into the mouse tissue. Within a matter of days, clusters of specialized immune cells formed in the infected areas.

“Typical immune responses deplete local specialized immune cells,” said Massberg. “It appears that the hematopoietic stem cells initiate an immune response and replenish these specialized immune cells. It’s a way of sensing local environmental disturbances and responding locally.”

Ultimately, the researchers identified the molecular mechanism that explains these data.

After residing for a while in the organ tissue, the stem cells receive a lipid signal that enables them to exit into the thoracic duct. But when receptors on the stem cell surface that detect the pathogens become active, the cell’s ability to receive the lipid signal is blocked. The stem cells get stuck in the tissue, where they are then triggered to differentiate into a variety of immune cells.

“That stem cells are actually a part of the immune system, rather than just giving rise to it, is a very provocative idea,” said von Andrian, the Edward Mallinckdrot Jr. professor of immunopathology at HMS. The researchers are now looking for ways that other common diseases, like cancer, might exploit this process.

—David Cameron

Image-based Screens Identify Cell-clearing Compounds

Using image-based high-throughput screens, HMS researchers, in collaboration with the Shanghai Institute of Organic Chemistry, have identified eight compounds that not only induce autophagy without causing cellular injury but also promote long-lived protein degradation.

Junying Yuan, HMS professor of cell biology and senior author of the study, and her colleagues screened nearly 500 known bioactive compounds before identifying the octet, which have surprising versatility. Of the eight compounds, seven have already been approved by the Food and Drug Administration for various antipsychotic and cardiovascular treatments.

“We wanted to pick out the ones that were truly inducing autophagy,” Yuan said. “We were very surprised that seven of the compounds were already approved by the FDA for drugs.”

Autophagy mediates the degradation of intracellular organelles and long-lived proteins through a lysosome-dependent mechanism. Research has shown that reduction of autophagy leads to the accumulation of misfolded proteins in neurons and may be involved in chronic neurodegenerative diseases.

While the study, appearing in the Nov. 27 Proceedings of the National Academy of Sciences, revealed eight regulators of autophagy, Yuan and colleagues encountered some compounds that only promoted certain aspects of the mechanism. Many compounds, for example, were found to induce autophagy as a result of causing cellular damage. Other compounds induced the accumulation of autophagosomes by blocking downstream lysosomal functions, thereby preventing the degradation process.

“It is important to know if you can find compounds that can increase autophagy without causing cell death,” said Yuan, referring to the popular drugs tamoxifen and rapamycin, which both can activate autophagy but have the side-effect of causing apoptosis.

If researchers can promote the process of autophagy without causing cell injury, they could potentially treat neurodegenerative disorders like Alzheimer’s and Huntington’s diseases.

In the case of Huntington’s, autophagy may be able to help clear the accumulation of misfolded proteins. Indeed, in cultured cells, seven of the eight autophagy inducers decreased the accumulation of expanded polyglutamine—the product of the infamously toxic CAG repeats found in Huntington’s patients.

After identifying the eight compounds through a series of image-based screens, which involved techniques to measure autophagical characteristics such as growth and relied on green fluorescent protein and other markers, the researchers analyzed their pathways to see whether they were identical to that of the apoptotic rapamycin. This drug leads to autophagy by targeting an enzyme inhibiting signals for cell cycle progression, cell growth, and proliferation. Yet the only commonality the eight compounds shared with rapamycin was their ability to induce the autophagical process; none of them followed rapamycin’s pathway.

True regulators of autophagy will be able to induce the digestion of misfolded proteins in neurodegenerative disorders, said Yuan. One of the identified regulators, trifluoperazine, is effective in the symptomatic relief of chorea, especially in Huntington’s patients. Since seven of the eight compounds already have the FDA’s approval for other uses, Yuan said, researchers are eager to study them further and determine their treatment requirements for misfolded-protein removal.

“What you need to do is to activate autophagy once in awhile,” said Yuan. “Hopefully, that’s all you have to do to clear your mind.”

—Laura Geggel

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